DESCRIPTION: Coronary artery disease (CAD) is a major cause of morbidity and mortality in human worldwide. Recent interest has focused on chronic infectious diseases like periodontal infection as potential contributors to CAD since traditional risk factors like hypercholesterolemia, smoking and hypertension fail to fully explain the incidence of CAD in populations. Epidemiological studies indicate that individuals with periodontal infection are 30 to 100% more likely to have CAD; however, it remains possible that confounding factors account for these observations and mechanistic studies to explain this connection are lacking. Periodontal disease is associated with a state of systemic inflammation, and a likely target for circulating cytokines and oral pathogens is the vascular endothelium, which plays a central role in the regulation of vascular homeostasis. Activation of endothelial cells by inflammatory cytokines promotes a pro-atherogenic phenotype with increased expression of inflammatory factors and loss of the anti-thrombotic, growth inhibitory, and vasodilator properties of the endothelium. These changes occur early in the development of atherosclerosis and contribute to the pathogenesis and clinical expression of disease. The purpose of this application is to test the hypothesis that the host inflammatory response plays a primary role in infection-aggravated atherosclerosis and investigate the specific signaling mechanisms that account for this process. The Specific Aims of this application are: Aim 1. To determine the relative importance of systemic inflammation versus direct bacterial invasion of the arterial wall for atherosclerotic lesion formation. Aim 2: To determine whether inhibition of Toll-like Receptor 2 (TLR2) and IL-1 receptor pathways limits atherogenesis following bacterial challenge. Aim 3: To determine whether activation of TLR2 and IL-1 receptor pathways aggravate atherosclerotic plaque formation. Aim 4: To determine whether a mouse model of bacterial periodontitis exacerbates atherosclerosis. The proposed studies will provide mechanistic insights into how Porphyromonas gingivalis contributes to atherosclerosis formation and progression. The long-term goal of this application is to develop therapeutic strategies aimed at controlling the deleterious effects of the inflammatory response in atherosclerosis.